The Shift Toward Evidence-Based Medicine - The Role of Community-Based Guidelines

OBJECTIVE: To review evidence-based medicine (EBM), how it emerged, how it works, and what drug utilization patterns across the United States would look like if we applied EBM methods to this population. SUMMARY: There is a collective presumption about the overuse of pharmaceuticals, unchallenged by any substantive data, that has become part of American folklore: high drug use by people in this country actually represents overuse. This pre-sumption is completely unfounded. On the contrary, a recent analysis carried out by the RAND Corporation indicated that fewer than 70% of people in the United States with chronic illness receive adequate medical treatment. CONCLUSIONS: The flow of almost all medical research strongly supports the conclusion that more medicine is better. EBM has ably pointed out that too many patients receive unneeded diagnostic and surgical procedures. It will also demonstrate that too few patients receive appropriate medical care.


Table of Contents
The Shift Toward Evidence-Based Medicine-The Role of Community-Based Guidelines

Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the U.S. Food and Drug Administration. The Postgraduate Institute for Medicine (PIM), Dover Communications, Amgen, Inc., and Wyeth do not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient' s conditions and possible contraindications on dangers in use, review of any applicable manufacturer' s product information, and comparison with recommendations of other authorities.  vidence-based medicine (EBM) is defined as a process that attempts to identify and use the best available evidence, which includes data from observational as well as randomized prospective studies. The result, ideally, is not cookbook medicine, but a matter of obtaining the best available information about therapies and combining this with the physician' s own clinical experience and patient-specific factors and preferences.
The advocates of EBM concede that their approach can lead to increased costs in the case of some individual patients or diseases. Dealing with costs is, however, part of the work of the pharmacy and therapeutics (P&T) committees that have to decide which therapies are best suited to their institutions. This is a job that is complicated by differences in clinical test design and the absence of a standard threshold of what is cost effective. A new therapy that has demonstrated great effectiveness in clinical trials may not always be the "best buy" for a given institution after due consideration of such factors as routes of administration, complex scheduling, monitoring requirements, potential adverse effects, the patient' s quality of life, and the likelihood of rebound or relapse when therapy is discontinued.
P&T committees must generally make their decisions on the basis of incomplete information, before sufficient postmarketing information about new therapies has become available. There are very few reports on head-to-head comparisons of 2 drugs, and often the patient populations in various clinical trials are not comparable or very similar to the patients in a health care institution. Information that would be useful for cost-effectiveness decision making is also often not included in published studies. The committees also need pharmacoeconomic (PE) data that must be weighed against the potential clinical benefits and disadvantages-a task that is complicated by the availability of several different PE models. New PE models are developed all the time and are likely to be more complicated than those now in use.
Effective treatments may not always be more economical than other treatments, and this has led to assertions that EBM will actually lead to the use of more drugs and an increase in the costs of treatment. Some commentators, in fact, regard EBM as a medical fad based on the false assumption that the increased availability of new drugs must mean that drugs are being overused. Data from clinical trials are one of the foundations of EBM, and its critics cite data showing that only about two thirds of Americans suffering from chronic illnesses are adequately medicated-and that even though studies of surgical practices have shown wide regional variations, the same is not true of the use of prescription drugs in different parts of the country. Psychological factors may also play a part in the current popularity of EBM inasmuch as P&T committee members often came of professional age in the 1980s and 1990s, when the overuse of antibiotics constituted a real problem, direct-to-consumer advertising of prescription drugs began, and new drugs became available for many conditions.

TARGET AUDIENCE
Pharmacists and pharmacy administrators working in a managed care environment

LEARNING OBJECTIVES
Upon completion of this program, participants will be better able to 1. explain how community-based guidelines support evidence-based medicine, 2. discuss the role of pharmacoeconomic measures and modeling in the establishment of community-based standards of care, and 3. discuss medical treatment selection based on EBM criteria versus drug acquisition costs alone.

I N T R O D U C T I O N
J.D. KLEINKE; DANIEL C. MALONE, RPh, PhD; and PAUL N. URICK, RPh R emember "six sigma?" In the 2000-2002 period, it was health care' s Next Big Idea, preoccupying its restless technocracy as the Health Insurance Portability and Accountability Act (HIPAA)-generated anxiety was waning and "consumer-driven health care" had yet to reach its current frenzy. Six sigma was and still is an important industrial engineering methodology developed by General Electric over several decades of practice and experimentation. As year-2000 (Y2K) and HIPAA conversions came and went, with great effort but none of the devastations predicted by the technocrats, six sigma filled an important void for the health care consulting industry in its eternal quest to generate billable hours.
The goal of six sigma in its original context was to reduce the incidence of manufacturing production errors to 6 per 100,000 production units. It was never clear, when applied to health care, what a six sigma "production unit" might represent. Was it the care of one patient with a chronic illness over a period of time? An isolated episode of care experienced by that patient at one medical facility? Or any one of the hundreds of products and services that might be administered to that patient during that one episode?
When asked about this at a public event, the leader of a major health care consulting practice-after singing the praises of six sigma methodology-was not sure. Not that it mattered. The consultant and those in the audience never had to go through the obvious methodological difficulties inherent in translating a manufacturing accounting exercise to medical care. The idea of measuring and managing the medical treatment of human beings with complex illnesses as though they were light bulbs moving along an assembly line was absurd enough for the health care technocrats to abandon six sigma as quickly as they adopted it, en masse, and move along to the Next Big Idea.
As of this writing, health care' s Next Big Idea is "evidence-based medicine (EBM)." Exactly like six sigma, EBM is a legitimate, quantitative discipline that was invented and honed over decades for a very specific purpose-and has since been co-opted for a completely different purpose. Since health care' s current folk wisdom is focused almost obsessively on the erroneous twin beliefs that drugs are (1) overused in the United States and (2) singularly responsible for rising health care costs, EBM-as applied to pharmaceutical use-has been seized upon as the next messiah coming to save the U.S. health care system from itself. Its champions view EBM as a way to rein in what they perceive as the overuse of drugs.
Because the EBM "fix" and the problems themselves are all steeped in folk wisdom rather than actual empirical reality about drug use and health care costs, this mindless rush to sham EBM is merely the latest expression of American society' s resentment of the pharmaceutical industry for its success and a deeper frustration with the chronic cost, inefficiency, and equity problems in health care in general. Those who would use EBM to rein in the ever-expanding use of newer and better drugs-and thus reduce the costs associated with their use-are not interested in empirical reality, appropriateness, or any of the other ideals underlying the true EBM movement; they are desperate for a way to justify rationing but do not have the political courage to use the R-word.
Even the most casual review of EBM' s methods, in conjunction with an honest review of the literature of drug utilization across the U.S. population, reveals that EBM, as it is applied to pharmaceutical use, is a high-minded-sounding smokescreen for rationing care without saying as much. If EBM' s methods were applied to actual utilization patterns, EBM would expand rather than restrict the use of drugs, both across and within therapeutic classes. Nonetheless, the make-work exercise that is pharmaceutical EBM has come to dominate the policy-making activities of state Medicaid agencies and PBMs that seek ever newer and more intellectually defensible ways to restrict patients' access to care.
This article, as a direct confrontation with these agencies' alleged realpolitik, is intended to provide a badly needed reality check. Stripped of its current political packaging, what is EBM? When and why did it emerge? How does it really work? And what would drug utilization patterns across the United States look like if we applied EBM methods to a population that we know, according to actual EBM analyses conducted for nonpolitical reasons, is actually undermedicated?

II Evidence-Based Medicine 101
Before analyzing the soundness of applying EBM methods to pharmaceutical use, it is important to review the origins and conclusions of those methods. In its original incarnation, EBM involved the use of longitudinal empirical outcomes analyses to measure, in retrospect, the usefulness of diagnostic and surgical procedures. It is important for society to measure the outcomes associated with such procedures specifically because they do not undergo the same clinical testing, prior to their introduction into mainstream medical care, that drugs undergo prior to their approval by the U.S. Food and Drug Administration (FDA).
One needs to look no further than at the continuing struggle, after nearly 15 years of study, over whether or not Pap smears and mammograms actually reduce, respectively, long-term cervical and breast cancer mortality rates. The answers, according to EBM studies still in progress, vary greatly by age group (e.g., 40+ years versus 50+ years), periodicity (e.g., annual versus biannual), and myriad other risk factors for the disease. Judging by the literature, it seems that no two researchers can agree on any conclusion, at least not over time. This lack of agreement about the usefulness of clinical interventions, endemic to all of medicine, provides the crucial entry point for EBM' s newest champions, who argue that any intervention is guilty of uselessness until proven innocent The EBM movement was presaged in John Wennberg' s groundbreaking work on variations in surgical procedures in the late 1980s. 1 Within adjacent counties in Vermont, Wennberg discovered 4-, 5-, and 6-fold differences in the utilization of common surgical procedures like tonsillectomy and prostatectomy. Although it was technically not EBM because of its absence of outcomes data, Wennberg' s work on "small-area variations" unleashed a cottage industry of research on variation analysis, enlivening the careers of several dozen physician-researchers. 1 At first, the identification of such variations implied overuse; these phenomena were decoupled by Lucian Leape and colleagues in a landmark study of small-area variations of surgical procedures in 1990, during the cresting of the variations analysis wave unleashed by Wennberg and the wave of EBM to follow. 2 One of the core assumptions of those who would apply EBM to drug use is that drug utilization patterns, when finally studied, would surely mirror the sloppy, uneven, and occasionally bizarre utilization patterns of diagnostic and surgical procedures uncovered by the EBM movement. EBM methods would show physicians how and how often their knee-jerk prescribing habits were inappropriate, the same way those methods have shown surgeons how and how often their propensity to operate has been inappropriate.
The goal of all EBM has been to add rationality to the clinical decision making of a medical community that, despite all its training and technology, engages in what often looks like folk art. Objective measures of medical practice, in a political vacuum, frequently reflect this notion. Such a vacuum does not account for things like defensive medicine, which is practiced to avoid frivolous medical malpractice lawsuits and thus compels the overuse of diagnostic testing, nor does it account for the dysfunctional economics of fee-for-service medicine, which compels the overuse of surgical procedures. This has led to the conclusion of EBM advocates that physician prescribing must be subject to the same tendency toward overuse.
But some of the tools of actual EBM, when applied to prescribing, do not confirm this presumption. In multiple research studies, Robert Dubois and colleagues have shown that we do not have variations in drug use approaching anything like what we have found in surgery. 3,4 In one study of the medication of multiple disease states across California, the researchers found variations between highest and lowest rates of drug use of 1.3 to 1.4 times 4 -a sharp contrast to the many times greater differences in the rates of diagnostic and surgical procedures documented by Wennberg and others.
The reliability of these numbers is confirmed by other researchers with an obvious commercial desire to find drug use variation. Motheral and colleagues from Express Scripts, a large, national pharmacy benefits manager that would be able to use variations as a rationale for marketing its services, found variations in medication use across regions that ranged from 1.7 to 1.9 for most medication classes. 5 So much for variations. But what about overuse? In general and with a few obvious and important exceptions like antibiotics, EBM compels an expanded rather than restricted use of pharmaceuticals for almost every studied disease state. This is confirmed in a survey of the most broadly accepted published clinical guidelines, the real-world manifestation of EBM' s methods, in an analysis published in Health Affairs in January/February 2004. 6 Now for the more acute reality check. The core presumption of EBM-that drugs are guilty of uselessness until proven innocent-stands in direct opposition to how physicians are trained to treat patients. Bounded only by the "first do no harm" covenant of the Hippocratic Oath, physicians actively prescribe drugs that are proven in FDA-sanctioned clinical trials to work; to do so is to "treat empirically," meaning to try an individual drug on an individual patient to see if it works or not. (This is the clinically defensible part of the much-maligned practice of drug sampling, which further explains why the EBM' s "guilty until proven innocent" strategy finds such favor among antipharmaceutical industry policymakers who have co-opted EBM methods to justify their rationing mandates.) The misapplication of EBM' s methods to restrict drug use is further emboldened, mistakenly, by the occasional drug or drug class that proves, long after FDA approval and extensive utilization experience, not to lack efficacy (as the EBM champions generally believe) but actually to be implicated in potential adverse events. The most obvious and recent examples are the major reconsideration of hormone therapy and antidepressants in teenagers, along with the withdrawal of rofecoxib (a popular COX-2 inhibitor) in 2004. Such are the vagaries of a nation of physicians treating patients empirically. For many surgical and diagnostic procedures that are adopted into practice without the rigorous testing undergone by drugs, longitudinal, data-driven EBM-type analyses are often not favorable. For drugs that do undergo such testing, the actual evidence often goes the other way-the drugs not only work, they work overtime, and often result in additional, undesirable clinical effects.

II Drug Culture Shock
It is important to note that many individuals serving as medical directors and administrators in today' s public and private health care payer organizations came of professional age during the 1980s and 1990s, when the real EBM movement itself was coming of age. Consider the coincidence of this timing with the following phenomena, which occurred during the same time period: 1. a wave of studies showing widespread overuse of antibiotics, which has since grown into a very real public health problem; 2. rapid and sustained growth in the use of prescription drugs in general; 3. the introduction of highly visible and deeply controversial direct-to-consumer advertising of drugs in 1997; 4. the launch of new drugs to treat physiological and psychological disorders never before addressed medically; 5. a doubling in the size of the pharmaceutical industry between 1990 and 2000; and finally 6. maintenance of the profitability of that industry throughout the same decade, while the rest of the health care system is suffering from nearly identical economic crises at the beginning and end of the period. The aggregate result of this confluence of factors seems obvious and inevitable-a collective presumption about the overuse of pharmaceuticals, never challenged by any data, that has coalesced into folklore: because we Americans are using so many drugs all of a sudden, we must be using too many. Contrary to what today' s champions of applying EBM to drug use would have us believeand consistent with deep resentments of Americans about being forced to subsidize the drug care of the rest of the developed world-this presumption is pure fairy tale. According to an analysis of drug care by the RAND Corporation, only 68.6% of Americans with chronic illness are adequately medicated. 7 This is why a few years from now the EBM movement, as misapplied to drug use, will have passed through health care with the permanence and profundity of six sigma reengineering. It is an intellectually bankrupt idea that will implode for the same reasons it has emerged-the current misapplication of EBM reflects an obsessive determination to manage money, not outcomes, not evidence, and certainly not disease. As has been demonstrated during numerous other attempts to reduce health spending by limiting access to expensive drugs, which actually are our best tool for managing overall health care costs, the use of EBM is certain to backfire.
The flow of almost all medical research-basic and applied, prospective and retrospective, privately and publicly fundedmoves us in one direction: more medicine is better. That should be obvious to anyone who has actually read a medical journal or any newspaper account over the last decade about breakthroughs in biomedical science, the rise of protein engineering, continual improvements in diagnostic technologies, and the decoding of the human genome. All of these scientific moving parts go toward building an ever more vivid understanding of the human machine and, thereby, ever greater opportunities for manipulating and preserving that machine with biochemistry. EBM, while ably pointing out that too many patients receive diagnostic and surgical procedures they did not need, will prove only what we already know from numerous research endeavors-too few patients receive drug care, not too many.

DISCLOSURES
The author received an honorarium from Amgen, Inc., and Wyeth for participation in the symposium upon which this article is based. He discloses no potential bias or conflict of interest relating to this article.
vidence-based medicine (EBM) is designed to improve the quality of clinical decisions and improve patient outcomes. Sackett et al. define EBM as "the conscientious explicit and judicious use of current best evidence in making decisions about the care of individual patients." 1 EBM was developed to help clinical practitioners make better decisions about the therapies they prescribe, the procedures they perform, and the advice they give to patients. It is not intended to be onerous, but it requires clinicians to frame questions accurately, conduct literature searches to identify the evidence, and then make appropriate interpretations of that evidence.
Sackett et al. begin by stating that EBM is not cookbook medicine. 1 Rather, it is a process of obtaining the best available evidence and merging this with clinical expertise and patient-specific factors and preferences. Secondly, they state that EBM is not a panacea for controlling costs-that it may, in fact, lead to increased costs when these expenditures are for the most effective interventions to maximize the patient' s quality of life. Finally, they state that EBM is not based solely upon randomized trials or meta-analyses. The essence of EBM is to identify the "best" available information relevant to the question at hand. There are many more questions than answers in medicine today. Sackett et al. specify that practitioners of EBM should have good clinical interviewing skills, be self-directed life-long learners, and maintain humility in clinical practice because, without it, physicians "become immune to self-improvement and advances in medicine." 1

II Why Are Pharmacoeconomic Evaluations Important in the Context of EBM?
Although pharmacoeconomics (PEs) involves processes similar to EBM, it deals with decisions on the population level and not the patient level. The overall goal of PE is to provide the most efficient use of resources, taking into account both the cost and the value derived from using a technology. The factor driving the use of PE is monetary. Resources are scarce and many innovative products are expensive. This is especially true as we move from small molecule medications to therapies based upon proteins and DNA techniques. Biological agents are much more difficult to manufacture because of issues related to potency, stability, and packaging. The person evaluating PE information needs to understand the limitations of PE studies and not expect them to provide the answers to all questions of interest. In this sense, PE contributes information to the decision process, but it does not supplant clinical and safety data.
The basis for PE studies is usually derived from clinical trials conducted as part of the drug-development process. The standards necessary for market approval are often at odds with the data needed by clinical decision makers. Consequently, manufacturers must weigh the time and cost of conducting PE studies.
In a PE context, those studies in which patients are randomized to treatment arms, both the patients and observers are blinded, and an active comparator is included are of higher value than similar studies conducted using placebo or no treatment arms. From a technology assessment perspective, nontreatment is not common, and may be unethical. Randomized studies are the gold standard because they control for threats to internal validity. In theory, randomized studies are less likely to be invalid because of systematic bias. 2 Not as useful are observational studies where treatments are not randomly assigned. These studies are often conducted in a pre-post fashion and may or may not have a control group. Many observational studies suffer from "confounding by indication," where patients are assigned to a therapy group because of the severity of their illness. A specific medication may be used because the severity of disease warrants its use. In such studies, comparisons between medications, even those in the same class, may not be appropriate because the patient groups are inherently different. 6 present an excellent opportunity to examine the cost-effectiveness of new therapies. These large studies typically involve patient populations that are more reflective of usual clinical practice, and the protocols often require only usual medical care monitoring. In this sense, they tend to reflect "effectiveness" rather than "efficacy." Because of this, economic evaluations based upon these studies can generally be applied to a broad variety of health care environments.

PE analyses can be based upon a variety of study types. The quality of the information used in cost-effectiveness analyses can range from large randomized controlled trials (RCTs) to observational studies. Large trials, such as GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), 3 CLASS (Celecoxib Long-term Arthritis Safety Study), 4 VIGOR (Vioxx Gastrointestinal Outcomes Research), 5 and 4S (Scandinavian Simvastatin Survival Study)
A step-down from large RCTs are economic studies based upon meta-analysis of smaller clinical trials. These analyses are slightly less desirable because the study sample is frequently more limited. In addition, protocol-induced utilization and monitoring can influence the economic results. Economic studies based on a single RCT are even less desirable. This is true of many economic analyses, especially those performed at the time the product is initially marketed. Because these are based on only a single study, these analyses must be interpreted with caution because the results may not fully reflect the "effectiveness" of a given product when it is prescribed by a variety of health care providers.
At the other end of the spectrum are observational studies, often based upon an analysis of medical and pharmacy claims. These frequently lack measures of clinical effectiveness because the study populations were assembled for administrative, not clinical, reasons. Despite this limitation, these studies can be useful in examining the economics of multiple medications as they are used in everyday clinical practice. Many practitioners of EBM tend to discount the value of observational studies. This is not always advisable, as Smith and Pell demonstrate in discussing the evidence to support the use of parachutes for "gravitational challenge." These authors conducted a literature search for published RCTs involving the use of parachutes and state, as a challenge to the use of only RCTs for EBM: Advocates of evidence-based medicine have criticized the adoption of interventions evaluated using only observational data. We think that everyone might benefit if the most radical protagonists of evidence-based medicine organized and participated in a double-blind, randomized, placebo controlled, crossover trial of the parachute. 7

Because members of pharmacy and therapeutics (P&T) committees often make decisions in the absence of perfect data, the question of error arises. In this context, the data needed to make informed decisions are a function of the risk being undertaken. For questions of safety and efficacy, only high-quality studies should be used. However, as one moves from safety to coverage and purchasing decisions, the tolerance of error can increase.
As a further illustration, when a product' s safety profile is questionable, a P&T committee may choose to wait until phase IV studies are completed before adding it to the formulary. The consequences of this decision are not only to deny the therapy to some patients who may benefit but also to prevent the occurrence of potentially negative outcomes such as severe morbidity or death. On the other hand, if a decision is made to add a medication to the formulary on the basis of its perceived cost-effectiveness and a subsequent analysis suggests that the medication was not worth the additional cost, the harm induced is often only financial. This is not to belittle the potential financial consequences of decisions but rather to illustrate that all decisions are likely to include a degree of error. In the end, every health plan must determine its own tolerance of uncertainty in adopting new technologies.
Cost-effectiveness analysis (CEA) is the most common economic analysis conducted for pharmaceuticals. It centers around the additional cost and value gained by using a new technology relative to usual medical care, which can be a pharmaceutical, a procedure, or no treatment. Thus, for CEA, the incremental cost-effectiveness ratio (ICER) is most desirable. Many CEAs are piggybacked onto clinical trials where both cost and efficacy or effectiveness are determined within a subset of subjects. Because there is a sample to draw upon for an estimate of the mean cost and efficacy, these studies are referred to as stochastic-"involving or containing a random variable." An economic analysis based upon an RCT often has a high degree of internal validity due to randomization and blinding of patients and observers. Common disadvantages include the lack of an active comparator (many studies are placebo comparative), a relatively short study

duration, and protocol-induced utilization and monitoring. An example of stochastic CEA is an analysis of the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late
Angioplasty Complications) trial, which evaluated the use of abciximab in coronary revascularization. 8 In this study, data on the use of health care resources were collected on a subset of hospital billing records. The outcome of interest was quality-adjusted life-years. Because both costs and outcomes were based upon an actual trial, the resulting economic analysis was completely stochastic.
Stochastic data are often not available because the economic analysis is being conducted after the completion of pivotal trials or access to the data from clinical studies is not permitted. This often happens in attempts to compare products of different manufacturers. In such cases, economic analyses are often based upon deterministic data-defined as precisely limited or defined data.

These analyses typically involve the use of a measure of central tendency, such as a mean or median. Cost data for these types of studies are often limited, relying upon an estimated price based upon typical dose and frequency of administration. By definition, deterministic economic studies fail to capture the inherent variability in medical care. That said, they can often contribute to discussions about the adoption of new technologies. An example of a deterministic cost-efficacy study is a comparison involving the use of etanercept or infliximab for the treatment of disease-modifying antirheumatic drug-resistant (DMARD) patients
with rheumatoid arthritis. 9 This particular analysis was based upon 2 separate clinical trials that evaluated these products. 10,11 Both studies enrolled patients with similar inclusion/exclusion criteria. The data for medical costs were based upon the U.S. Food and Drug Administration-approved dosing regimens and average wholesale prices (AWP).
The primary outcome was the cost per patient achieving a 50% improvement according to the American College of Rheumatology criteria (ACR50). The analysis suggested that etanercept was more cost-effective than infliximab because of its higher efficacy and lower cost. Etanercept supplies were limited at the time of this particular economic analysis and, as a result, many managed care plans could only use infliximab. Consequently, the economic analysis assumed that infliximab was the current treatment and that etanercept was the new technology.
In comparing etanercept with infliximab in terms of costeffectiveness, etanercept was a dominant strategy relative to infliximab. The major limitation of this type of analysis is that cost-effectiveness results are based on deterministic data. Threshold analyses to determine where the decision would change from etanercept to infliximab showed, in one case, that the efficacy of infliximab 3 mg/kg every 8 weeks would need to improve from 21% to 44% of patients achieving an ACR50.
Often, economic analysis indicates that a new therapy costs more but is more effective than the therapy it is replacing. In those situations, the adoption of the new therapy depends on the health plan' s willingness to pay for the incremental value. Unfortunately, no widely accepted standards for what is "cost-effective" existespecially when the analysis is conducted with natural or clinical outcome as the denominator. Figure 1 displays a hypothetical cost-effectiveness threshold for a health plan in terms of accepting or rejecting a new pharmaceutical. Deterministic CEA will generate a single estimate of the ICER, which we will assume falls on the upward sloping line. With a stochastic cost-effectiveness study, the resulting ICERs would have some variation and the shape of the 95th percentile confidence intervals would become an oval (Figure 2). Figure 2 also shows that the shape of the oval is a function of the relationship between cost and effect, with a negative relationship resulting in a larger difference between the upper and lower bounds. Therefore, the decision to adopt a new medical technology can be influenced by the type of cost-effectiveness study.

The Role of Pharmacoeconomic Modeling in Evidence-Based and Value-Based Formulary Guidelines
Health care organizations find themselves in the unenviable position of having to decide what is and is not cost effective. There are 2 approaches that an organization or program may use when determining which technologies to purchase. The first is an absolute budget constraint rule whereby all health care technologies would be ranked and the most cost-effective technologies would be adopted first. This would continue until the entire budget was consumed and is essentially what was implemented in the Oregon Medicaid program. The other approach is to use a relative budget constraint rule where the organization would adopt all technologies whose cost fell below a stated threshold. The problem with a relative budget constraint rule is that an organization could exhaust its entire budget on cost-effective therapies.

II Summary
EBM is a process that attempts to identify and use the best available evidence, which includes observational as well as randomized prospective studies. Economic studies are usually based on data from clinical trials. These evaluations can assist health care payers in the decision-making process because both cost and effectiveness are considered. More manufacturers are incorporating economic data collection into the clinical trial design, but decision models are still common. New therapies are becoming more complex in terms of administration, effects, and cost. As a result, PE models are likely to become more complex. Finally, there is no standard threshold of what is cost effective, so each organization is likely to have its own threshold of acceptance. Research can provide estimates of what is cost effective but cannot determine whether a given technology represents a good buy for a specific organization. Ultimately, that is a line in the sand that has to be crossed by the purchaser.

DISCLOSURES
The author received an honorarium from Amgen, Inc., and Wyeth for participation in the symposium upon which this article is based. He discloses that he is a consultant to Amgen. T here is general agreement that results from well-controlled clinical trials should guide selection of therapy for routine clinical practice. Evidence-based medicine (EBM) has emerged as a paradigm for the practice and teaching of clinical medicine, and it focuses on procurement and interpretation of clinical research in order to choose the most efficacious diagnostic procedures and therapies. 1 This approach to selection of therapy has been driven by both the need to cope with information overload and the requirement to control the cost of therapy. 2 Many considerations must be taken into account when translating EBM into formulary and clinical guidelines. The aim of this paper is to briefly review the steps that should be followed in the progression from consideration of therapeutic options on the basis of EBM to formulary decisions and implementation of clinical guidelines. This review carefully considers each of these steps and their components, providing specific examples of this progression.

EBM is aimed at determining the clinical value of a given therapy. Clinical value is the primary determinant of whether a given drug should be included in a formulary and/or recommended in a clinical guideline.
A number of different features must be considered together in determining the clinical value of a given therapy. These include the product profile, its prescribing information (i.e., U.S. Food and Drug Administration-approved labeling), clinical trial data that is peer reviewed and published, dosage and route of administration, mechanism of action, the prevalence and epidemiology of the clinical condition it is used to treat, the clinical manifestations of that disease, and both clinical and postmarketing data documenting clinical efficacy and safety.

II Pharmacoeconomic Considerations
The second step in the progression from clinical evidence to formulary and clinical guidelines is pharmacoeconomic analysis. This can be accomplished using a variety of models. The discipline of pharmacoeconomics can be defined as the science of measuring the costs and outcomes associated with the use of pharmaceuticals in health care delivery to a patient population. The main purpose of pharmacoeconomic evaluation is to compare the costs and consequences of therapeutic alternatives. There are 4 main types of pharmacoeconomic evaluations: cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), cost-minimization analysis (CMA), and cost-utility analysis (CUA). All of these methods compare treatment alternatives, often a new therapy versus the current standard of care. 3,4 It is important to note that pharmacoeconomic analysis is a step that plans may consider in this process and is not, in itself, a sole determinant of formulary or clinical positioning.
In CBA, both costs and benefits of a treatment are measured in monetary values, with future costs and benefits discounted to their current value. Although this is considered the best approach to economic analysis, its application in pharmacoeconomics and general health care is limited because of difficulties in assigning a monetary value to health outcomes and the life of a patient. 4 CEA compares therapeutic alternatives with different efficacy and safety profiles. Costs are calculated in monetary value and outcomes are determined as clinical values (e.g., decline in blood pressure for an antihypertensive agent or number of cases cured for an antibiotic). In lifetime CEA, outcomes are measured as years of life gained with the new treatment versus the current standard of care. 4 CMA is employed to determine the least expensive treatment among alternatives with presumably equivalent efficacy and safety profiles. CMA should contain elements necessary to factor the costs of care other than the direct cost of the unit prescription product. 4 In CUA, cost is measured in dollars and outcomes are measured in "quality-adjusted life-years" (QALYs) gained. This measure of treatment utility incorporates both quantity and quality of life. 5 The use of QALYs to define outcomes permits comparison among cost-utility ratios from different pharmacoeconomic analyses. The least-costly treatment alternative is that with the lowest cost per QALY. 4

II Formulary and Clinical Guidelines
The purpose of formulary and clinical guidelines is to optimize patient care. Formularies and guidelines should undergo a process of continual reevaluation in order to improve the overall quality of care. Establishment and updating of formulary and clinical guidelines requires close collaboration among health care professionals, attention to national guidelines, evidence-based assessment of treatment alternatives, and authoritative endorsement based on both peer review and the deliberations of Pharmacy & Therapeutics (P&T) committees.
Pharmacists coordinate P&T committee activities with a priority on clinical value. They may take several approaches to incorporating pharmacoeconomics into formulary decisions. Published pharmacoeconomic studies from the primary literature may be extracted and evaluated, and many approaches have been proposed for the critical evaluation of pharmacoeconomic literature. 4,6 If there are no pharmacoeconomic studies available, the P&T committee may decide to perform an analysis using published data from randomized, controlled studies of efficacy and safety. A cost-effectiveness ratio can be determined by computing all relevant costs for each alternative under consideration.
Many hospitals and health care organizations have treatment guidelines for the management of specific diseases. Pharmacists are often involved in guideline development. This process begins with a comparison of the efficacy and safety profiles of available treatments based on results from clinical trials. The multidisciplinary process involves physicians, pharmacists, and administrators and may also require pharmacoeconomic evaluation. 4 Pharmacoeconomic studies may guide clinicians in making cost-effective choices for specific categories of patients, but these choices may not be the most cost effective for each individual patient. Pharmacoeconomic analysis is designed to evaluate the costs and benefits of different therapies that will be delivered to large numbers of patients with clearly defined characteristics. In practice, patient-specific factors (e.g., drug allergies, comorbid conditions) can make the most cost-effective agent a very individual choice. 4,7 Physicians and pharmacists need to carefully assess individual patient factors as well as population-based analysis in order to effectively translate principles derived from pharmacoeconomics to actual clinical practice. 4

II Clinical Guidelines
In many hospitals and institutions, local treatment guidelines are implemented for specific disease states. Pharmacists are often involved in developing treatment guidelines, policies, and protocols. As in formulary inclusion, the process of establishing guidelines starts from the evaluation of the available treatments and comparison of efficacy and safety profiles derived from clinical trials data. The aim is to provide the correct therapy for each patient and to deliver that intervention at the appropriate time. The development of clinical guidelines requires consideration of diagnostic, treatment, drug utilization, and reauthorization criteria, if applicable. Diagnostic criteria identify indications that constitute acceptable uses for a formulary drug. The P&T committee should establish any protocols restricting use to specific diagnoses and conditions. Treatment criteria identify approved drugs for use in specific labeled indications as well as total episodes of care based on sound principles. Drug utilization criteria identify approved frequency and/or length of product administration, sequencing of utilization, and duration of therapy.

II Case Studies
This section includes 2 case studies designed to illustrate application of the principles considered in the preceding sections. The first involves the use of 3-hydroxy-3 methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) to treat hypercholesterolemia and reduce the risk for cardiovascular events in primary and secondary prevention. The second study deals with the use of new highly targeted biologic agents to treat patients with psoriasis.

Treatment of Hypercholesterolemia
There is strong evidence linking hypercholesterolemia to increased risk for cardiovascular disease, and many studies have shown that statin therapy significantly reduces levels of plasma cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), and also lowers the risk for cardiovascular events in both primary and secondary prevention. Implementing Community-Based Standards of Care 6,505 men and women without documented coronary heart disease (CHD) who were followed for an average of 5.2 years. 8 Similarly, results from the West of Scotland Coronary Prevention Study (WOSCOPS), which included 6,595 men with no history of myocardial infarction (MI) who had elevated total cholesterol levels, showed that treatment with pravastatin decreased the risk of CHD-related death by 33%. 9

Secondary Prevention
Results from several trials have also demonstrated the ability of statin therapy to decrease the risk of cardiovascular events in patients with documented CHD. Findings from the Cholesterol and Recurrent Events (CARE) trial, which included 3,583 men and 576 women with a history of MI and elevated total cholesterol and LDL-C, indicated that treatment with pravastatin reduced CHD-related mortality by 24%. 10 Results from the Scandinavian Simvastatin Survival Study (4S), a trial that included 4,444 patients with angina pectoris or previous MI and elevated total cholesterol, showed that the relative risk for CHD death was reduced by 42% for patients who received simvastatin. 11 Results from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial, which included 9,014 patients with a history of MI or hospitalization for unstable angina, indicated a 24% reduction in relative risk for CHD-related death among patients who received pravastatin. 12 Yusuf has summarized the relationships between LDL-C and cardiovascular risk from these studies (Figure 1), and the results demonstrate a strong benefit in reducing LDL-C levels as secondary prevention and a smaller benefit in primary prevention. 13 All of these results are consistent with those from more recent clinical trials that have demonstrated the effectiveness of statin therapy in patients with acute coronary syndromes. 14,15

The Guidelines
The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) focuses on reducing LDL-C levels as the primary goal of lipid-lowering therapy. Target LDL-C levels differ according to a patient' s 10-year CHD risk (Table 1). A goal of <100 mg/dL is suggested for patients with CHD or its risk equivalents (other clinical forms of atherosclerotic disease or diabetes that confer a >20% chance of CHD within 10 years, according to the Framingham scoring system). Individuals without CHD but with ≥2 risk factors (cigarette smoking, hypertension, high-density lipoprotein cholesterol [HDL-C] <40 mg/dL, family history of premature CHD, age ≥45 years for men and ≥55 years for women) should aim for an LDL-C <130 mg/dL. The goal for individuals without CHD and <2 risk factors is <160 mg/dL. 16 A very recent update of these guidelines advocates even more aggressive treatment of hypercholesterolemia, particularly in high-risk patients. It is now suggested that the target for LDL-C should be <70 mg/dL in patients at very high risk for cardiovascular events. 17 Relationship Between CHD Events and LDL-C Levels in Major Trials 13

Pharmacoeconomics
Aggressive implementation of the NCEP ATP III guidelines, according to current estimates, would result in more than 36 million Americans being considered eligible for lipid modification via drug therapy. 18 Unlimited use of LDL-C lowering drugs, although potentially clinically effective in reducing CHD risk, would be costly, and limited resources must be targeted to provide the greatest health benefits. Economic analysis facilitates patient selection to maximize incremental benefits relative to incremental costs.
Formal economic analysis of the most recent clinical trials with statins suggests that secondary prevention of CHD is very cost effective in comparison with existing treatment and prevention strategies. Primary prevention is also cost effective to a lesser degree and has a much wider range of cost-effectiveness depending on individual baseline risk. Cost-effectiveness can be better maximized in primary prevention by treating patients at the highest absolute risk of CHD (Table 2). 19

Use of Biologic Agents to Treat Psoriasis
Psoriasis is one of the more common forms of chronic dermatitis in the world. This disease affects about 6 million people in the United States alone and has marked negative physical and psychological impacts on patients. 20 The overall cost of treating patients with clinically significant disease has been estimated to be $649.6 million each year. 21 Until recently, no systemic therapies were suitable for long-term treatment of psoriasis because of the high risk for toxicity. 22 It is now understood that T-cells and the cytokines they secrete play central roles in the pathogenesis of psoriasis, and new targeted biologic agents have been developed for treatment of this disease. 22 A consensus statement from the American Academy of Dermatology recommends that biologic agents may be considered among the first-line treatment options in patients who are candidates for systemic therapy and that such treatment may be appropriate for patients with psoriasis on the palms and soles, head and neck, or genitalia, or when the disease involves >5% of the skin surface. 23 Three new agents that have been used effectively for the treatment of psoriasis are alefacept, efalizumab, and etanercept (Table 3). [24][25][26] Alefacept is a fully humanized LFA-3/IgG1 that binds to CD2 and thus prevents the activation of T-cells. Clinical trial results have demonstrated that alefacept provides responses that are sustained for up to 18 months in patients with psoriasis. 27 Efalizumab is a recombinant humanized IgG1 that binds to CD11a, inhibiting the binding of T-cells to other cells as well as T-cell activation. This monoclonal antibody has also been shown to be effective for the treatment of patients with psoriasis. 25,28 Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kD (p75) tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1. Etanercept binds specifically to TNF and blocks its interaction with cell surface TNF receptors. The naturally occurring TNF cytokine is involved in normal inflammatory and immune responses, and plays an important role in a wide range of inflammatory immune system diseases, including rheumatoid arthritis (RA), polyarticular-course juvenile rheumatoid arthritis (JRA), ankylosing spondylitis (AS), and psoriasis. 24 Etanercept has been shown to be highly effective for treatment of patients with psoriasis. 29 While all of these new agents are effective for the treatment of patients with psoriasis, they do differ in a number of parameters (